CONFORMATIONAL STUDIES OF NEW ANTITUMOR AGENTS

药物分子的构象与其分子的构象是初始相关的。 功能 这项研究将确定药物的潜在限制 实验性抗肿瘤剂噻唑弗林和 硒偶氮呋喃。 硫唑弗林（TF）和硒唑弗林（SF）是新的碳糖基 目前正在进行临床试验的核苷。 在体内，TF和 SF被并入辅因子NAD的类似物中。 这些 NAD类似物作为一磷酸肌苷的抑制剂 脱氢酶，细胞毒性的假定原因。 晶体 TF和SF的结构显示出它们之间不寻常的密切接触， 碱基中的杂原子（S或Se）和呋喃糖环氧， 这表明这些试剂和/或它们的构象 NAD类似物可被限制在溶液中。 这将 对药物结合和活性的重要影响。 计算结果表明，杂原子氧 相互作用部分是静电作用。 因此， 杂环电荷和糖基键构象将 在一系列新的碱取代类似物的噻唑- 和硒偶氮弗林。 晶体学、计算和NMR 将采用技术。 晶体学数据库综述 显示分子内紧密联系的化合物 为了进一步确定其起源， 杂原子-氧相互作用 NMR实验采用 各种质子和异质结技术将检查 母体化合物和NAD类似物在 溶液 酶抑制和建模研究将调查 NAD类似物与其他辅酶A酶的结合， 将结合能力与糖基键的变化相关联 构象

The conformation of a drug molecule is initimately related to its function. This research will identify potential constraints on drug conformation in the experimental antitumor agents tiazofurin and selenazofurin. Tiazofurin (TF) and selenazofurin (SF) are new C-glycosyl nucleosides currently undergoing clinical trials. In vivo, TF and SF are incorporated into analogues of the cofactor NAD. These NAD analogues act as inhibitors of inosine monophosphate dehydrogenase, the putative cause of cytotoxicity. Crystal structures of TF and SF show unusual close contacts between the heteroatom in the base (S or Se) and the furanose ring oxygen, suggesting that the conformations of these agents and/or their NAD analogues may be restricted in solution. This would have important implications for drug binding and activity. Computational results suggest that the heteroatom-oxygen interaction is in part electrostatic. Thus, the correlation between heterocycle charge and glycosyl bond conformation will be examined in a series of new base-substituted analogues of tiazo- and selenazofurin. Crystallographic, computational and NMR techniques will be employed. A crystallographic data base survey of compounds showing close intramolecular contracts will be performed in order to further identify the origins of the heteroatom-oxygen interaction. NMR experiments employing a variety of proton and heteronuclear techniques will examine the conformation of the parent compounds and the NAD analogues in solution. Enzyme inhibition and modeling studies will investigate binding of the NAD analogues to other dehydrogenases and correlate binding ability with changes in glycosyl bond conformation.